(1) Field of the Invention
The present invention relates to a hollow fiber membrane for the dialysis of blood, having a highly-improved function of removing solutes and a good compatibility with blood.
(2) Description of the Prior Art
At the present, hollow cellulosic fibers for the dialysis of blood are widely used as dialysis membranes for an artificial kidney. An artificial dialyzer comprising this membrane gives an appropriate ultrafiltration rate and a high clearance of low-molecular-weight substances, and functions excellently to prolong the life of a patient. However, developments in medical techniques have made it desirable to provide a high-performance membrane which exerts not only the life-prolonging effect but also an effect of making it possible for a patient to live and work in society in the same way as a healthy man, when the patient does not receive dialytic treatment. More specifically, removal of not only low-molecular-weight substances but also middle-molecular-weight and high-molecular-weight substances is now desired, and researches are being carried out to develop dialysis membranes capable of sufficiently removing middle-molecular-weight and high-molecular-weight substances in a short time without causing an unpleasant feeling in a patient.
From the hematological viewpoint, in conventional membranes, an immunological disorder such as activation of the complement or temporary decrease of leukocytes is regarded as a problem, and in order to prevent coagulaton of blood at the dialysis, it is necessary to use a considerable amount of an anti-coagulant, which sometimes gives an unfavorable side effect. Accordingly, development of a membrane not causing these biochemical troubles is strongly desired.
As means for overcoming the defects of the conventional membranes, there has been proposed a membrane prepared by a wet phase-inversion process using a synthetic polymer. According to the principle of this wet process, the permeability to substances to be removed is not manifested by the molecular structure of the synthetic polymer used but by a secondary structure formed according to appropriate membrane-forming conditions. Namely, the permeability is manifested by exposing a solution of the synthetic polymer dissolved in a solvent to a nonsolvent for the synthetic polymer while controlling the state of precipitation of the synthetic polymer by the composition of the solvent, the temperature, and the composition of the nonsolvent. In the membrane prepared according to the wet phase-inversion process, voids among the precipitated particles of the synthetic polymer act as passages for substances to be removed, whereby the permeability is manifested.
As the membrane of this type, there have been proposed a polyacrylonitrile membrane, a polysulfone membrane, a polymethyl methacrylate membrane, and a polycarbonate-polyethylene glycol membrane. Because of the membrane-forming principle, the ultrafiltration rate in these membranes is too high, and therefore, a special apparatus (UFR controller) for controlling the amount of water to be removed must be used at the dialysis and the operation becomes complicated. A polycarbonate-polyethylene glycol membrane in which the polyethylene glycol content is about 30% by weight, so as to lower the ultrafiltration rate by rendering the membrane hydrophilic, is proposed. Where a high polymer is rendered hydrophilic, when the polymer is exposed to a nonsolvent therefor and the formed membrane is dried by air drying or the like, the membrane is drastically shrunk and the permeability is extremely reduced. Accordingly, it is not permissible to dry the membrane according to customary procedures.
Furthermore, even when a seemingly dry product is obtained by using a wetting agent such as glycerol, if it is allowed to stand for a long time, the size and dialytic activity are changed with the lapse of time and hence, the membrane cannot be regarded as being appropriate as a membrane for the dialysis of blood. Moreover, even when membranes are prepared from the foregoing polymers including the above-mentioned copolymer having a low polyethylene glycol content, as is apparent from the micro-phase-separation-conformation thereof, no practical permeability can be manifested. Still further, since the permeability is controlled according to membrane-preparing conditions, the control must be performed very carefully, and since a solvent is used, a treatment is necessary for removal of the solvent after the formation of a membrane. In short, the membraneforming process is very complicated. In addition, almost all membranes prepared according to the conventional techniques are unoriented membranes consisting of aggregates of particles, and therefore, the mechanical strength is ordinarily poor and there is a risk of the leakage of blood at the blood treatment. A solvent capable of dissolving a synthetic polymer therein has a good compatibility with the synthetic polymer. Therefore, even if the solvent-removing treatment is carried out, it is very difficult to completely expel the residual solvent, and a satisfactory membrane for the dialysis of blood cannot be obtained. From the hematological viewpoint, a polyacrylonitrile membrane, a polysulfone membrane, and a polymethyl methacrylate membrane exert effects of moderating the activation of the complement and the temporary decrease of leukocytes. However, adverse influences to the living body, such as the adhesion of platelets to the membrane, are sometimes caused. Accordingly, these membranes are not hematologically satisfactory.
As means for overcoming the defects of the conventional membranes, there has been proposed a process for preparing a membrane for the dialysis of blood according to the melt membrane-forming method from a poly-.epsilon.-caprolactam-polyalkylene ether-polyacyl lactam block terpolymer having poly-.epsilon.-caprolactam blocks and polyalkylene ether blocks (European Patent Publication No. 6030). However, it is not proved that this poly-.epsilon.caprolactam-polyalkylene ether-polyacyl lactam block terpolymer sufficiently eliminates the defects of the conventional membranes. This block terpolymer is formed by connecting 35 to 65% of the polyalkylene ether component with acyl lactam and can be regarded as a block copolymer of poly-.epsilon.-caprolactam (nylon 6) and polyalkylene ether. Each of the components of this copolymer has a water absorption of at least 1% and is hydrophilic. Accordingly, a membrane prepared from this block copolymer is highly hydrophilic and, if the polyalkylene ether content is increased to improve the dialyzability, the wet mechanical properties of the membrane in water or an aqueous solution such as blood are lower than those of a membrane prepared by using a hydrophobic component as one component.
When this block copolymer is melt-spun, the copolymer is treated at a temperature sufficient to melt the copolymer. It is predicted that low-molecular-weight nitrogen-containing compounds will be generated by oxidative degradation or thermal degradation of the copolymer at this treatment. If this membrane is used for a blood treatment, such as dialysis, it is thought that these low-molecular-weight nitrogen-containing compounds will have an adverse affect on the living body. Moreover, this block copolymer is not sufficiently improved with respect to the immunological disorder, that is, the activation of the complement. Accordingly, the membrane of this copolymer cannot be regarded as being satisfactory as a blood treatment membrane.
As is apparent from the data of sample E in Examples III and IV in European Patent Publication No. 6030, the membrane prepared according to the solution-casting process is different from the membrane prepared according to the melt-spinning process in the solute permeability, and the latter membrane has a much lower solute permeability. Namely, the permeability to urea is reduced to about 1/2 and the permeability to vitamin B-12, which is a typical instance of the middlemolecular-weight or high-molecular-weight substance, is reduced to about 1/5. When an oriented membrane is obtained by drafting or drawing an ordinary synthetic high polymer at a temperature higher than the heat distortion temperature, the above tendency is ordinarily observed. Where all the components of a block copolymer are hydrophilic, because of the good compatibility among the block segments, during the course of from the melted state to the solidification by cooling, advance of the phase separation necessary for manifestation of the solute permeability is delayed as compared where one component of the block copolymer is hydrophobic. Thus, it is expected that a domain conformation will be finally formed. It is believed that this promotes the above-mentioned tendency.
D.J. Lyman et al have proposed in Biochemistry, Vol. 3, No. 7, July 1964 a solution-casting process for forming a membrane for the dialysis of blood, in which a polyethylene terephthalate-polyethylene glycol block copolymer comprising a polyethylene glycol having a low molecular weight of 600 to 4000, which is included in the block copolymer comprising an aromatic polyester and polyoxyethylene, used in the present invention, is dissolved in dichloromethane at a copolymer concentration of 15 to 20% by weight, the solution is cast on a glass sheet and air-dried, the glass sheet is put into water and the formed membrane is peeled from the glass sheet. It is set forth in this reference that the correlation between the composition of the block copolymer and the dialyzability depends upon not the molecular weight of the polyethylene glycol but the content thereof. According to the solution-casting membrane-forming process, because of the solubility of the copolymer with the solvent, it is very difficult to completely remove the residual solvent, and the formed membrane is not satisfactory as a blood-treating membrane.
In order to moderate the burden on a patient at the step of circulation of blood outside the body, it is necessary to reduce the quantity of blood to be taken from the body to a level as low as possible. A suggestion of the use of hollow fibers effective for this purpose is not found in the proposal of Lyman et al. Moreover, the formation of hollow fibers according to the solution-casting membrane-forming process is very difficult, and additional steps such as the step of recovering the used solvent become necessary and the manufacturing cost will be increased. A membrane prepared according to the solution-casting membrane-forming process is substantially unoriented and the block copolymer obtained according to the teaching of Lyman et al has a reduced viscosity lower than 1.5. Accordingly, this membrane does not have sufficient strength enough to show the good bursting resistance required for a membrane of a blood dialyzator, especially a flat membrane.